Whereas the great majority of primary keratoplasties succeed in human beings, and intolerable high proportion of allogeneic corneas grafter into"high-risk" eyes fail. Immune rejection is regarded as the major cause of graft failure. Our long term goal is to understand the cellular and molecular immune processes that dictate (a) why primary orthotopic corneal allografts are so well tolerated, and (b) why grafts placed in "high-risk" eyes fare so poorly. Our experimental approach is to conduct and analyze orthotopic corneal allografts in inbred strains of mice. To guide us in our experiments, we have formulated two related hypotheses: (1) Because the normal cornea is deficient in professional antigen presenting cells, induction of systemic immunity to alloantigens on orthotopic corneal grafts occurs almost exclusively via recipient antigen presenting cells - the so-called indirect pathway of antigen presentation. (2) allografts are more likely to suffer rejection in high-risk eyes because the ocular tissues, including the cornea itself, fail to provide an immunosuppressive intraocular microenvironment. We describe three Specific Aims: 1. Evaluate interactions between varying degrees of immunogenetic disparity and risk factors for refection of orthotopic corneal allografts in mice. 2. Delineate pathways of T cell recognition of alloantigens expressed on orthotopic corneal grafts. 3. Determine the extent to which ocular tissues, especially cornea, of "high-risk" eyes fail to create and sustain a local immunosuppressive microenvironment. Our experiments will generate results that should help to elucidate the roe of immune privilege in the extraordinary success of keratoplasties, the contribution that loss of privilege to "high-risk" eyes, and would minimize the immunogenicity of the critical alloantigens responsible for graft failure.